Integrins are a superfamily of heterodimeric transmembrane glycoproteins that function in cellular adhesion, migration and signal transduction. These glycoproteins consist of an α and a β-subunit, which associate non-covalently in defined combinations. To date, 17 α-subunits and eight β-subunits have been identified, which associate selectively to form at least 23 integrins, all of which appear to function as receptors.
The integrin αvβ3, also referred to as the vitronectin receptor, is expressed on a variety of cell types, including osteoclasts, vascular smooth muscle cells, endothelial cells and various tumor cells. In general, the level of expression of αvβ3 integrin is low on most cell types but it is greatly increased in remodeling or growing tissues. Consistent with its expression profile, αvβ3 integrin mediates several biologically relevant processes, such as adhesion of osteoclasts to bone, vascular smooth muscle cell migration and angiogenesis. As a result, vitronectin receptor antagonists are useful for the treatment of endometriosis, osteoporosis, restenosis following percutaneous transluminal coronary angioplasty (PTCA), rheumatoid arthritis, cancer and ocular diseases [see, e.g., Miller et al., Identification and in vivo efficacy of small-molecule antagonists of integrin αvβ3 (the vitronectin receptor), Drug Discovery Today, Vol, 5, No. 9, 397-408 (2000)].
Osteoporosis is a debilitating bone disease characterized by a decrease in bone mass (osteopenia) leading to an increased risk of fracture. The osteopenia associated with osteoporosis arises from an imbalance between bone resorption and formation, such that resorption exceeds formation. For bone resorption to occur, the bone-resorbing osteoclasts must first adhere to the bone matrix and this key adhesive event is mediated by αvβ3 integrin. Disruption of osteoclast adhesion inhibits bone resorption both in vitro and in vivo and provides a therapeutic approach to the treatment and/or prevention of osteoporosis [see, Miller et al. (2000)].
Angiogenesis (the formation of new blood vessels) involves the αvβ3 integrin mediated migration and proliferation of endothelial cells. Significantly, the vitronectin receptor is upregulated only in growing vessels and not in mature ones. Thus, vitronectin antagonists are useful in the treatment of diseases characterized by excessive or undesirable angiogenesis, such as cancer, rheumatoid arthritis, diabetic retinopathy and macular degeneration. In support of this hypothesis, vitronectin-selective antibodies and peptides have been shown to be effective inhibitors of angiogenesis [see, Miller et al. (2000)].
U.S. Pat. No. 6,306,819 describes the use of angiogenesis inhibitors in vivo for obesity, intestinal polyps, cardiac hypertrophy, and endometriosis. Initial studies conducted in genetically obese mice showed that inhibition of angiogenesis led to reduction in adipose tissue mass. Weight gain in animals receiving angiogenesis inhibitors was significantly reduced, in spite of increases in appetite sufficient to cause weight gain in paired-fed mice. Discontinuation of the inhibitor resulted in rapid expansion of the adipose tissue. The effect was dose-dependent, repeatedly reversible, and occurred in response to all of the inhibitors tested. Significant inhibition was also observed in both the intestinal polyp and cardiac hypertrophy animal models. Results in vivo in an endometriosis model also showed decreased development of endometriosis in animals treated with angiogenesis inhibitors.
Rheumatoid arthritis is a debilitating, systemic autoimmune disease in which there is massive bone and cartilage destruction within articulating joints. Integrin αvβ3 is expressed on the vessels within the invasive pannus and appears to play a role in angiogenic vessel formation within the highly invasive hypertrophic synovium. In addition, vitronectin mediates the bone resorption process. Because rheumatoid arthritis involves both angiogenic vessel formation and bone resorption, vitronectin antagonists provide therapy for rheumatoid arthritis. A cyclic αvβ3 integrin inhibitor (an Arg-Gly-Asp peptide) has been shown to be effective in vivo in a rabbit model of inflammatory arthritis [see, Miller et al. (2000)].
Restenosis refers to a significant, delayed loss of blood vessel lumen that generally occurs after percutaneous transluminal coronary angioplasty (PTCA). Vascular smooth muscle cell migration into the neointima is a necessary step in restenosis and αvβ3 integrin, which is expressed on smooth muscle cells, has been shown to mediate this migration. In addition, vascular injury induced by PTCA causes a rapid, persistent and coordinated upregulation of αvβ3, αvβ5 and osteopontin during the period of neointimal development. Studies have shown that blocking the vitronectin receptor inhibits smooth muscle cell migration and that both peptide antagonists and a humanized monoclonal antibody are effective in reducing neointimal hyperplasia following arterial injury in vivo [see, Miller et al. (2000)]. Based on these findings, persons of skill accept that vitronectin antagonists would be useful for the treatment of restenosis following PTCA.